The sigma-1 receptor chaperone as an inter-organelle signaling modulator

Inter-organelle signaling plays important roles in many physiological functions. Endoplasmic reticulum (ER)–mitochondrion signaling affects intramitochondrial calcium (Ca2+) homeostasis and cellular bioenergetics. ER–nucleus signaling attenuates ER stress. ER–plasma membrane signaling regulates cytosolic Ca2+ homeostasis and ER–mitochondrion–plasma membrane signaling regulates hippocampal dendritic spine formation. Here, we propose that the sigma-1 receptor (Sig-1R), an ER chaperone protein, acts as an inter-organelle signaling modulator. Sig-1Rs normally reside at the ER–mitochondrion contact called the MAM (mitochondrion-associated ER membrane), where Sig-1Rs regulate ER–mitochondrion signaling and ER–nucleus crosstalk. When cells are stimulated by ligands or undergo prolonged stress, Sig-1Rs translocate from the MAM to the ER reticular network and plasmalemma/plasma membrane to regulate a variety of functional proteins, including ion channels, receptors and kinases. Thus, the Sig-1R serves as an inter-organelle signaling modulator locally at the MAM and remotely at the plasmalemma/plasma membrane. Many pharmacological/physiological effects of Sig-1Rs might relate to this unique action of Sig-1Rs.